CN106902362A - 一种用于超声引导的麻醉药物制剂及其制备方法 - Google Patents
一种用于超声引导的麻醉药物制剂及其制备方法 Download PDFInfo
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Abstract
本发明涉及一种用于超声引导的注射用麻醉药物制剂及其制备方法,其中包括超声造影剂、麻醉剂、抗氧化剂和pH调节剂,且pH值为6.5‑7.2。所述麻醉药物制剂将超声造影剂与麻醉剂组合使用,在进行麻醉剂注射的同时在体内注入超声造影剂,避免多次注射给患者带来的伤害和恐惧感,减少并发症的发生几率。注入体内后,在麻醉剂起效的同时,超声造影剂产生增强显像的效果。所述麻醉药物制剂具有良好的稳定性、有效性和安全性。
Description
技术领域
本发明涉及一种用于超声引导的麻醉药物制剂及其制备方法,属于药物制剂领域。
背景技术
随着超声技术的不断进步,医学超声的应用日益广泛,尤其是在传统的影像学以外领域的应用正在逐步增加,其中超声技术在临床麻醉中的应用发展迅速,已成为临床研究的热点之一。一方面是由于高分辨率便携式超声仪器和探头技术的改进,使超声从单纯的临床诊断走进了手术室;另一方面,随着传统的麻醉方法越来越不能满足临床的要求,客观上也需要临床麻醉进行技术革新,而超声的无创性、实时性、可视性以及可重复性等特点恰好能为临床麻醉的术前评估、术中监测、部位麻醉以及疼痛治疗提供精确的数据和丰富的手段。
在临床麻醉中,神经阻滞广泛应用。神经阻滞定位有解剖定位、异感定位、神经刺激器定位、放射学定位等。传统方法神经阻滞需要借助体表解剖标志、动脉搏动、寻求异感或采用神经刺激器探查定位,存在的问题是主观上需要操作者经验丰富,对解剖知识非常熟悉,麻醉技术要求高,客观上要求患者能够配合操作者的指令。即便这样,仍有将局麻药注入到血管引起严重的并发症和后遗症的可能性。
近年来,广泛开展了超声技术在外周神经阻滞中的应用,超声成像技术能直接观察神经及其周围的结构,实施精确的神经阻滞,避免损伤周围组织及血管,保证局麻药的准确注射,使药物均匀扩散到神经周围,提高了神经阻滞的准确率,使周围神经阻滞达到满意的效果。尤其对小儿肢体手术麻醉能提高神经阻滞成功率和减少并发症。超声引导神经阻滞的应用已相当广泛,如肌间沟路、锁骨下路、腋路臂丛神经阻滞,下肢有腰丛神经阻滞、股神经阻滞、腘神经阻滞、隐神经阻滞、踝部胫神经阻滞,其他的神经阻滞如肌皮神经阻滞。
超声技术在临床麻醉中应用的多种优越性使其跃升为麻醉医生的“第三只眼睛”,高质量的超声显像能保证麻醉医生迅速精准定位,进一步提高麻醉的准确性。
在临床诊断中,为提高超声成像的分辨率和灵敏度、提高图像质量、增强对比度和准确性,在人体内注射一种对比增强介质,即为超声造影剂。它通过改变组织的超声特性(如背向散射系数、衰减系数、声速及非线性效应等),对超声波束产生强烈的散射作用,从而使所在部位的回声信号显著增强,表现为声图像上图像灰度增强,从而达到提高图像对比度和清晰度的目的,有利于医生在神经阻滞过程中作出更为准确的判断和定位。
目前,现有技术中尚且没有将超声造影剂与麻醉剂组合制成药物制剂的报道。
发明内容
本发明的一个目的是提供一种用于超声引导的注射用麻醉药物制剂,其中包括5-10%(v/v)的超声造影剂,0.3-2.5%(m/v)的麻醉剂,4%-6%(m/v)的抗氧化剂,适量pH调节剂,且pH值为6.5-7.2。
在一个实施方案中,所述超声造影剂为微泡超声造影剂。
在一个实施方案中,所述麻醉剂选自利多卡因、普鲁卡因、罗哌卡因或苯佐卡因中的一种或多种。
在一个实施方案中,所述抗氧化剂选自亚硫酸钠、焦亚磷酸、硫代硫酸钠、维生素E或抗坏血酸中的一种或多种。
在一个实施方案中,所述pH调节剂选自氢氧化钠、碳酸钠、碳酸氢钠、磷酸氢二钠或者磷酸二氢钠中的一种或多种。
在一个实施方案中,所述pH值为6.8-7.0。
在一个实施方案中,所述pH值为6.8。
在一种实施方案中,所述麻醉剂为利多卡因;所述抗氧化剂为1:2的维生素E和抗坏血酸的组合;所述pH调节剂为碳酸氢钠。
在一种实施方案中,所述微泡超声造影剂可以为市售的微泡超声造影剂。
在一种实施方案中,所述注射用麻醉药物制剂为冻干粉针剂,其中还包括冻干保护剂。
在一种实施方案中,所述冻干保护剂选自无水乳糖、山梨醇或甘露醇中的一种或多种。
在一种实施方案中,所述冻干粉针剂的制备方法包括如下步骤:
(1)按配方量将抗氧化剂和冻干保护剂溶解于注射用水中,搅拌至完全溶解后,加入配方量的麻醉剂,搅拌至完全溶解,用适量pH调节剂调节pH至6.5-7.2的范围内,加入0.05%-0.1%(g/ml)的活性炭常温吸附30-40min,过滤除炭,用0.22μm无菌微孔滤膜过滤除菌;
(2)在无菌状态下加入微泡超声造影剂,搅拌均匀,并迅速进行半成品检验,检验合格后进行灌装;
(3)将步骤(2)中所得的半成品以1-2℃/分钟速度降温至-40~-45℃预冻3-5h,将预冻好的药液抽真空至15-20Pa,然后在8-10小时内匀速缓慢升温至-20℃,保温2-3小时,再在4-6小时内匀速升温至0-5℃,将升华完毕阶段结束后的药液在3-5小时内匀速升温至20-25℃,保温干燥2.5-4小时,检测合格后包装入库。
有益效果:
(1)本发明的用于超声引导的麻醉药物制剂将超声造影剂与麻醉剂组合使用,在进行麻醉剂注射的同时在体内注入超声造影剂,避免多次注射给患者带来的伤害和恐惧感,减少并发症的发生几率。注入体内后,在麻醉剂起效的同时,超声造影剂产生增强现象的效果。
(2)本发明的麻醉药物制剂经过对辅料、pH值范围的筛选,使得超声造影剂与卡因类麻醉剂达到良好的兼容性,冻干制剂复溶后形成稳定的混悬剂,具有良好的稳定性。
具体实施方式
还可进一步通过实施例来理解本发明,其中所述实施例说明了一些制备或使用方法。然而,要理解的是,这些实施例不限制本发明。现在已知的或进一步开发的本发明的变化被认为落入本文中描述的和以下要求保护的本发明范围之内。
抗氧剂的筛选
本实验考察了不同抗氧化剂对所述用于超声引导的麻醉药物冻干粉针剂冻干前以及冻干复溶后溶液性质的影响。
表1.不同抗氧化剂对所述用于超声引导的麻醉药物冻干粉针剂冻干前后溶液性质的影响
结论:以维生素E:抗坏血酸1:2的组合物作为抗氧化剂制得的冻干粉针剂复溶后溶液的物理性状更为稳定。
pH值范围的筛选
本实验考察了不同pH值对所述用于超声引导的麻醉药物冻干粉针剂冻干前以及冻干复溶后溶液性质的影响。
表2.不同pH值对所述用于超声引导的麻醉药物冻干粉针剂冻干前后溶液性质的影响
结论:冻干前溶液的pH值范围在6.5-7.2之间制得的冻干粉针剂复溶后溶液的物理性状更为稳定。
在本发明中,所述微泡超声造影剂的制备方法为:将10mg的DPPC(二棕榈酰磷脂酰胆碱)加入到约10ml的10%(w/w)甘露醇水溶液中;在65℃下加热该混悬液15分钟,然后冷却至室温。将全氟庚烷(8%v/v)加入到水相中,然后用高速均浆器将其乳化1分钟。然后将乳剂1200rpm离心10分钟,回收分离的小丸,以初始体积的10%甘露醇水溶液再混悬该乳剂。将乳剂收集到冻干玻璃瓶中,冷冻干燥即得。
实施例1
一种用于超声引导的麻醉药物冻干粉针剂,包括6%(v/v)的微泡超声造影剂,1.5%(m/v)的利多卡因,4%(m/v)的维生素E:抗坏血酸1:2混合抗氧化剂,适量碳酸氢钠且pH值为6.8,适量无水乳糖;
其制备方法包括如下步骤:
(1)按配方量将维生素E、抗坏血酸和无水乳糖溶解于注射用水中,搅拌至完全溶解后,加入配方量的利多卡因,搅拌至完全溶解,用适量碳酸氢钠调节pH至6.8,加入0.05%(g/ml)的活性炭常温吸附35min,过滤除炭,用0.22μm无菌微孔滤膜过滤除菌;
(2)在无菌状态下加入配方量的微泡超声造影剂,搅拌均匀,并迅速进行半成品检验,检验合格后进行灌装;
(3)将步骤(2)中所得的半成品以1.5℃/分钟速度降温至-45℃预冻3h,将预冻好的药液抽真空至20Pa,然后在10小时内匀速缓慢升温至-20℃,保温3小时,再在5小时内匀速升温至2℃,将升华完毕阶段结束后的药液在4小时内匀速升温至20℃,保温干燥4小时,检测合格后包装入库。
实施例2
一种用于超声引导的麻醉药物冻干粉针剂,包括8%(v/v)的微泡超声造影剂,2%(m/v)的罗哌卡因,5%(m/v)的维生素E:抗坏血酸1:2混合抗氧化剂,适量碳酸钠且pH值为7.2,适量无水乳糖;
其制备方法包括如下步骤:
(1)按配方量将维生素E、抗坏血酸和无水乳糖溶解于注射用水中,搅拌至完全溶解后,加入配方量的罗哌卡因,搅拌至完全溶解,用适量碳酸钠调节pH至7.2,加入0.05%%(g/ml)的活性炭常温吸附40min,过滤除炭,用0.22μm无菌微孔滤膜过滤除菌;
(2)在无菌状态下加入配方量的微泡超声造影剂,搅拌均匀,并迅速进行半成品检验,检验合格后进行灌装;
(3)将步骤(2)中所得的半成品以1.5℃/分钟速度降温至-40℃预冻4h,将预冻好的药液抽真空至20Pa,然后在8小时内匀速缓慢升温至-20℃,保温3小时,再在6小时内匀速升温至5℃,将升华完毕阶段结束后的药液在5小时内匀速升温至25℃,保温干燥4小时,检测合格后包装入库。
实施例3
一种用于超声引导的麻醉药物冻干粉针剂,包括9%(v/v)的微泡超声造影剂,2.5%(m/v)的普鲁卡因,5%(m/v)的维生素E:抗坏血酸1:2混合抗氧化剂,适量氢氧化钠且pH值为6.9,适量甘露醇;
其制备方法包括如下步骤:
(1)按配方量将维生素E、抗坏血酸和甘露醇溶解于注射用水中,搅拌至完全溶解后,加入配方量的普鲁卡因,搅拌至完全溶解,用适量氢氧化钠调节pH至6.9,加入0.1%(g/ml)的活性炭常温吸附40min,过滤除炭,用0.22μm无菌微孔滤膜过滤除菌;
(2)在无菌状态下加入配方量的微泡超声造影剂,搅拌均匀,并迅速进行半成品检验,检验合格后进行灌装;
(3)将步骤(2)中所得的半成品以2℃/分钟速度降温至-40℃预冻5h,将预冻好的药液抽真空至20Pa,然后在9小时内匀速缓慢升温至-20℃,保温2.5小时,再在5小时内匀速升温至3℃,将升华完毕阶段结束后的药液在4小时内匀速升温至22℃,保温干燥3小时,检测合格后包装入库。
实验例1
本发明制备的用于超声引导的麻醉药物冻干粉针剂按照稳定性实验指导原则以及冻干粉针剂有关规定进行稳定性实验,考察项目为外观、pH值、有关物质、可见异物及含量。
1.影响因素实验
将实施例1制备的冻干粉针剂在光照(45001x)、高温60℃条件下放置30天,于第0天、第5天、第10天和第30天取样,考察各项目指标的变化情况。参见表3。
表3:实施例1冻干粉针剂的影响因素实验结果
由上表可知,本品在影响因素实验条件下的测试结果符合有关冻干粉针剂的相关标准。
2.加速稳定性实验
将实施例1制备的冻干粉针剂按市售包装,将其在温度40℃±2℃、湿度75%±5%条件下放置,于第0、1、2、3、6个月取样测定。实验结果参见表4。
表4:实施例1冻干粉针剂的加速稳定性实验结果
由上表可知,本品在加速稳定性实验条件下的测试结果符合有关冻干粉针剂的相关标准。
3.长期稳定性实验
将实施例1制备的冻干粉针剂按市售包装,将其在温度25℃±2℃、湿度60%±5%条件下放置,于第0、3、6、9、12个月取样测定。实验结果参见表5。
表5:实施例1冻干粉针剂的加速稳定性实验结果
由上表可知,本品在长期稳定性实验条件下的测试结果符合有关冻干粉针剂的相关标准。
实验例2有效性和安全性
将实施例1中制备得到的冻干粉针剂复溶后得到均匀混悬液,将该混悬液以0.1ml/kg剂量注入新西兰白兔体内,达到麻醉状态后,在超声下观察,结果显示出明显增强各组织器官及神经的显像效果,并且维持约50-70分钟的有效增强时间。麻醉结束后,未发现任何不良反应。
由此,可以证明本发明的麻醉药物制剂具有良好的有效性和安全性。
本发明内容仅仅举例说明了要求保护的一些具体实施方案,其中一个或更多个技术方案中所记载的技术特征可以与任意的一个或多个技术方案相组合,这些经组合而得到的技术方案也在本申请保护范围内,就像这些经组合而得到的技术方案已经在本发明公开内容中具体记载一样。
Claims (10)
1.一种用于超声引导的注射用麻醉药物制剂,其特征在于,包括5-10%(v/v)的超声造影剂,0.3-2.5%(m/v)的麻醉剂,4%-6%(m/v)的抗氧化剂,适量pH调节剂,且pH值为6.5-7.2。
2.根据权利要求1所述的注射用麻醉药物制剂,其特征在于,优选的,所述超声造影剂为微泡超声造影剂。
3.根据权利要求1所述的注射用麻醉药物制剂,其特征在于,所述麻醉剂选自利多卡因、普鲁卡因、罗哌卡因或苯佐卡因中的一种或多种。
4.根据权利要求1所述的注射用麻醉药物制剂,其特征在于,所述抗氧化剂选自亚硫酸钠、焦亚磷酸、硫代硫酸钠、维生素E或抗坏血酸中的一种或多种;所述pH调节剂选自氢氧化钠、碳酸钠、碳酸氢钠、磷酸氢二钠或者磷酸二氢钠中的一种或多种。
5.根据权利要求1所述的注射用麻醉药物制剂,其特征在于,所述pH值为6.8-7.0。
6.根据权利要求1所述的注射用麻醉药物制剂,其特征在于,所述麻醉剂为利多卡因;所述抗氧化剂为1:2的维生素E和抗坏血酸的组合;所述pH调节剂为碳酸氢钠。
7.根据权利要求1所述的注射用麻醉药物制剂,其特征在于,所述微泡超声造影剂是市售的微泡超声造影剂。
8.根据权利要求1所述的注射用麻醉药物制剂,其特征在于,所述注射用麻醉药物制剂为冻干粉针剂,其中还包括冻干保护剂。
9.根据权利要求8所述的注射用麻醉药物制剂,所述冻干保护剂选自无水乳糖、山梨醇或甘露醇中的一种或多种。
10.一种根据权利要求8所述的注射用麻醉药物制剂的制备方法,其特征在于,包括如下步骤:
(1)按配方量将抗氧化剂和冻干保护剂溶解于注射用水中,搅拌至完全溶解后,加入配方量的麻醉剂,搅拌至完全溶解,用适量pH调节剂调节pH至6.5-7.2的范围内,加入0.05%-0.1%(g/ml)的活性炭常温吸附30-40min,过滤除炭,用0.22μm无菌微孔滤膜过滤除菌;
(2)在无菌状态下加入微泡超声造影剂,搅拌均匀,并迅速进行半成品检验,检验合格后进行灌装;
(3)将步骤(2)中所得的半成品以1-2℃/分钟速度降温至-40~-45℃预冻3-5h,将预冻好的药液抽真空至15-20Pa,然后在8-10小时内匀速缓慢升温至-20℃,保温2-3小时,再在4-6小时内匀速升温至0-5℃,将升华完毕阶段结束后的药液在3-5小时内匀速升温至20-25℃,保温干燥2.5-4小时,检测合格后包装入库。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1234742A (zh) * | 1996-10-28 | 1999-11-10 | 奈科姆成像有限公司 | 诊断和/或治疗剂的改进或与其相关的改进 |
WO2002060524A2 (en) * | 2001-01-30 | 2002-08-08 | Barnes-Jewish Hospital | Enhanced ultrasound detection with temperature dependent contrast agents |
CN1903187A (zh) * | 2006-03-21 | 2007-01-31 | 沈阳药科大学 | 含有局麻药的复方异丙酚注射剂及制备方法 |
CN102805874A (zh) * | 2012-07-19 | 2012-12-05 | 胡浩清 | 一种肛瘘超声造影液 |
-
2017
- 2017-02-13 CN CN201710075615.4A patent/CN106902362B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1234742A (zh) * | 1996-10-28 | 1999-11-10 | 奈科姆成像有限公司 | 诊断和/或治疗剂的改进或与其相关的改进 |
WO2002060524A2 (en) * | 2001-01-30 | 2002-08-08 | Barnes-Jewish Hospital | Enhanced ultrasound detection with temperature dependent contrast agents |
CN1903187A (zh) * | 2006-03-21 | 2007-01-31 | 沈阳药科大学 | 含有局麻药的复方异丙酚注射剂及制备方法 |
CN102805874A (zh) * | 2012-07-19 | 2012-12-05 | 胡浩清 | 一种肛瘘超声造影液 |
Non-Patent Citations (3)
Title |
---|
叶勇: "《制药工艺学》", 28 February 2014 * |
林海 等: "超声引导下C7星状神经节阻滞可行性研究", 《温州医科大学学报》 * |
潘卫三: "《工业药剂学》", 31 August 2015 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108578717A (zh) * | 2018-05-14 | 2018-09-28 | 郑宝生 | 一种超声引导用麻醉药物组合物及制备方法 |
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